Using a multi-modal imaging approach, we intend to investigate the impact of progesterone (PROG) and its neurosteroid metabolite, allopregnanolone (ALLO) on brain neurochemistry (gamma aminobutryic acid; GABA and glutamate; Glut concentrations), neuronal activation during working memory (dorsal lateral prefrontal cortex; DLPFC) and resting state connectivity (dorsal anterior cingulate; dACC and ventral striatum; VS). Nicotine dependence remains a critical public health issue in the United States, costing approximately 200 billion dollars each year in medical expenditures and lost productivity. Subgroups of Americans are unevenly affected by nicotine dependence as females compared to males are particularly at risk for the adverse health effects of nicotine dependence and individuals of lower versus higher socioeconomic status are more likely to smoke. Interestingly, the predominantly female sex hormone PROG exerts a positive effect on cognition and nicotine craving during abstinence and drug liking during re-exposure in both males and females, suggesting a possible therapeutic role for the hormone. Preclinical studies indicate that the effect of PROG in nicotine dependence would be mediated primarily through ALLO modulation of GABAergic function. To translate this line of investigation to the human laboratory, 50 men and 50 women with nicotine dependence will participate in a double blind, placebo-controlled crossover study of PROG that requires two abstinence trials (4 days each), smoking topography sessions and brain imaging (proton magnetic resonance spectroscopy; 1H-MRS and functional magnetic resonance imaging (fMRI; resting state and during cognitive task performance) pre and post each trial. PROG conversion to ALLO, which is modified by subject-level characteristics such as history of major depression, will be measured using standard GC-MS methods. Hypothesis-driven analyses examining dACC and connectivity with the striatum and prefrontal cortex will be examined using standard seed-based correlation analyses while DLPFC neurochemistry at rest and neural activation during working memory task performance are other primary outcomes. Brain imaging is conducted at the ultra-high magnetic field of 7 Tesla in order to maximize the signal to noise for 1H-MRS measurement of GABA and Glut, while allowing co-localization of regions of interest for the fMRI experiments. These brain imaging outcomes along with degree of conversion of PROG to ALLO, sex and smoking topography outcomes, will be provide critical new information regarding the potential for PROG/neurosteroids, as well as other GABA agonists, to be developed as treatments for nicotine dependence.